ABSTRACT Sickle cell disease (SCD) affects approximately 100,000 people in the United States and millions worldwide. Symptoms appear shortly after birth, and in less developed countries the majority of children with SCD die before the age of five. In the U.S., SCD patients suffer chronic pain and fatigue, severe acute painful crises requiring hospitalization and opiates, strokes, and multi-organ damage, and have an average mortality in their 40s. The only FDA approved drug for adults with SCD is the anticancer drug hydroxyurea. New treatments are desperately needed for both children and adults with SCD. SCD-101 is a botanical drug that inhibits red blood cell sickling in vitro and in vivo. The formation of sickle shaped red blood cells, caused by the polymerization of deoxygenated sickle hemoglobin, is the primary and causative event in the molecular pathogenesis of sickle cell disease; therefore, inhibition of sickling by SCD-101 should ameliorate the signs, symptoms, and slow the progression of sickle cell disease. In a Phase 1B study, SCD-101 was shown to be safe and reduced pain and fatigue, the two most common symptoms of sickle cell disease. The compounds in SCD-101 responsible for the antisickling activity are unknown, as is the mechanism of antisickling. Identification of the antisickling compounds would assist in clinical development and may enable the development of a more potent and effective drug for the treatment of sickle cell disease. Identification of the antisickling compounds would assist in the elucidation of the mechanism by which SCD-101 inhibits red blood cell sickling and point the way to a new target for antisickling drugs, and the development of a new class of compounds to treat sickle cell disease.